S-carboxyalkylene isothiuronium salts of antimonyl tartrate



Patented May 30, 1950 E 1): STATES? 2509,201 'S-GARBOXYALKXLENE ISOTHIURONIUM SALTS OF .ANTIMONYL TARTRATE Edmond E. Mo'or'e, -Waukegan, and.Le Roy W..

Clemenc'e; Highland lark, Ill., a'ssig'norstdAb M bottJLaboratorie's, North Chicago, 111., a corporationiof- Illinois.

, No Drawin Application August 22,1947;

Serial'No. 770,182

NET:

11 :.Claims:i-.- (Cl. 260-446);

Derivativesof .Anti'monyffl'page1190 This :process :involves reactingstwo moles-ofspotassium anL- timonyl tartratecwithione, :mole: ofiba'rium' chlo':- ride. The product obtained .usually has 3 moles"- The examples which follow will .:specify'-the more precise details-(L the process for the preparation of these compounds.

wherein is an;a1ky1.,;(a1ibh-afic hydrocarbon) S-a-carboxymethylisothiuronium antimonyl targroup containing from one to ten carbon' atoms. We have discoveredthat the compoundsof-the invention are active "chemotherapeutic agents.

They are of=particular 'valuein'thetreatment of 155:5

certain tropical parasitic diseases; e; g. in the treatment of schistosomiasisr We have also discovered that'thecompounds of the invention are soluble 'in Water: This is-of great practical importanceas-itmakes it possible to inject the compounds in an aqueous medium into the muscle for the treatment of a particular disease.

As a general processfor the preparation of these compounds; two molesof thealiphaticbasev or substituted isothiourea 'are: reacted--with ones mole of sulfuric acid andone mole-of :barium antimonyl tartrate. The sulfateoftha base; formed and the barium antimonyl tartrate-read trate NH HOOC.OHzS .SbOC4H4Oa NH AboutiADZcglnss.(0.030Hn01) EOfi'SideCMibOXYw': methyl-isothioureasiszcsuspended ain.:l5;0."ml. sof waev terl andircooled son: an iceaxbath:

M015 mole) of -bariumzzantiinonyl tartrate is added to the above solution and the mixture shaken vigorously for aboutnfifteen minutes in a closed container. The'resulting yellow solution is filtered and then centrifuged to remove all of ily undergo double decomposition so that the inso' h prec pitate. The.filtratesisrevapora ed u e soluble barium sulfate is "precipitated from the solution. After removal 'of the barium sulfate precipitate by a suitable means such as filtration,.the desired product may be. isolated by evapvacuum zat. art-temperature l-ofr. about 50 C;. The; white :solid :obtainediis broken tun r-and .was-hed withubenzene, ,1 redried zllndergvacuum: and-:washed; with:;absolute :ethylalcohol, Up on= ;redryingv the cratingv the aqueous solution to dryness; taking p =-fina1:product is a .pa1e- -yellow.solidi Analysisin-z the residue in a small amount of distilled water: and precipitating by the addition of alcohol. Instead of using the barium antimonyl tartrate, other alkaline earthmetalsalts such as the caldicatesa-am antimony content oft-28.65 The :cal-w culated percentage is '28 90% rantimony-t cium or strontium salts may be used. In fact, 40 5'5?eaTbowl/ethylisomwmmumiantimonyl anycombination maybe used, in.which theacid of any stable-acid-addition product 'williform a water insoluble product with the cation oia salt'i of antimonyl tartrate. For example, the oxalate" salt may be used with the calcium antimonyl tartrate by which;insolublescalcium"oxalate will precipitate from the aqueous solution. Thus the basic idea of the process of the invention is that theacid of the acid addition product must be insoluble with-the cation-of the antimonyl tar- About :.4'.44'- gms:-. (0.0?; r-moler) of. S-flecar-boxyethylisothioureads suspended in: 1001 -ml-.- of wa-.-'- ter and cooled;- on-:anicebath.- To this suspen-- sion is added 8.111111. (0.015 mole) of a 1:10 sulfuric acid solution prepared by"dissolving 10 ml. of concentrated.zsulfuriceacidzz and fdiluting with Water to a ovolumeuofwlflll ml.. Aiclearo solution results. About 11:44gms. (0.015 mole) of bariumantimonyltartrate is adde'd,.and the:resulting in thebook by-fihristiansen entitled,-fOrganic suspensioni isistirred and tl l'en'ifshakmi. Thesfil-cv To sthisiisradded v 8.41 LmL; ofmza cold :solutionaoi- 1 :11 0, ;lsulfuric .acid;i'

trate is centrifuged and then evaporated under vacuum in a vacuum drier at 50 C. resulting in a gummy mass. This mass is triturated with absolute ethyl alcohol containing benzene and the alcohol decanted. This trituration and decanting is repeated and the product dried again as above. Upon drying, the powder analyzes to lnicate a content of 27.46% antimony. The calculated antimony percentage for the compound EXAMPLE IV S -e-carboxy-namylisothiuronium antimonyl tartrate NH no 0 o cachet .sbo CIHlOO Using the procedure disclosed in Example I or II and using a ratio of two moles of S-e-carboxyn-amylisothiourea for one mole of sulfuric acid and one mole of barium antimonyl tartrate, the above compound is obtained. The antimony content is found to be 25.57%. The calculated antimony content is 25.59

EXANIPLE V S c carboxy-n-(y-methyl) -amylisothiuronium antimonyl tartrate By duplicating the procedure of Example I or II and by using a ratio of two moles of S-e-carboxy-n-(y-methyl) -amylisothiourea for one mole of sulfuric acid and one mole of barium antimonyl tartrate, the resulting product is the compound described above. The compound is found to have an antimony content of 25.3%. The calculated percentage of antimony is 24.85%.

EXAMPLE VI S-x-carbowy-n-decylisothiuronium antimonyl tartrate NH nooo. omiw.s.tt.sbo 0.11.0.

By replacing the substituted thiourea in the foregoing examples with S-x-carboxy-n-decylisothiourea, the above compound is obtained.

EXAMPLE VII Methylglucamine antimonyl tartrate CHzOH (CI-IOH) 4CH2NHCH3.SbOC4HeO6 About 5.85 gms. (0.03 mole) of methylglucamine is dissolved in 150 ml. of water andthe solution cooled in an ice bath. About 8.33 cc. (0.015 mole) of a 1:10 solution of sulfuric acid is added while the solution is being stirred. 11.44 gms. (0.15 mole) of barium antimonyl tartrate is next added and the mixture shaken for about 16 hours. The resulting suspension is filtrated and centrifuged to remove the barium sulfate from the solution. The filtrate is evaporated under vacuum at 50 C. The resulting oil is washed with absolute ethyl alcohol several times and with dry benzene once and redried under vacuum. A fine white powder results. This powder is found to have a content of 25.87% antimony. The calculated content is 25.32% antimony.

The substituted isothioureas used as intermediates may be prepared by processes described in the literature as follows: S-a-carboxymethylisothiourea; Journal American Chemical Society 63, 3531 (1941) and the publication of Moore et al., ibid., 69, 266 (1947 The compounds of the present invention may be incorporated into a number of suitable pharmaceutical vehicles. Since these compounds are water soluble they are most effectively prepared for intramuscular injection by dispensing the product as an aqueous solution. Concentrations up to 10% have been found to be satisfactory.

The term mole is intended to refer to gram molecular weight.

Others may readily adapt the invention for use under various conditions of service, by employing one or more of the novel features disclosed, or equivalents thereof. As at present advised with respect to the apparent scope of our invention, we desire to claim the following subject matter.

We claim:

1. S-carboxyalkylene isothiuronium salts of antimonyl tartrate.

2. Isothiuronium salts of antimonyl tartrate with the following formula:

1 111 HOOC.R.S.t).Sb0C4H0 wherein R is an alkylene group containing from one to ten carbon atoms.

3. The compound S-c-carboxymethylisothiuronium antimonyl tartrate with the following formula:

5. The compound S-e-carboxyamylisothiuronium antimonyl tartrate with thefollowing structure:

NH noodwnmattsbooimoi 6. The process of preparing organic carboxyalkylisothiuronium salts of antimonyl tartrate which comprises: reacting a carboxyalkylisothiuronium-acid addition product with a metal salt of antimonyl tartrate; said acid and said metal being of such a nature that they will form an insoluble precipitate with each other in water.

'7. The process of preparing carboxyalkylisothiuronium salts of antimonyl tartrate, which comprises: reacting a carboxyalkylisothiourea sulfate with barium antimonyl tartrate.

8. The process of preparing carboxyalkylisothiuronium salts of antimonyl tartrate, which comprises: reacting a carboxyalkylisothiourea with sulfuric acid and reacting the resulting isothiuronium sulfate with barium antimonyl tartrate.

9. The process of preparing carboxyalkylisothiuronium salts of antimonyl tartrat-e, which comprises: reacting two moles of a carboxyalkylisothiourea with one mole of sulfuric acid and reacting the resulting isothiuronium sulfate with one mole of barium antimonyl tartrate.

10. The compound S-6-carboxy-n-butylisothiuronium antimonyl tartrate with the following formula:

11. The compound S-e-carboxy-n-(v-methyD amylisothiuronium antimonyl tartrate with the following formula:

The following references are of record in the file of this patent:

UNITED STATES PATENTS Name Date Shonle May 24, 1938 OTHER REFERENCES Chemical Abstracts, vol. 16 (1922), page 611, abstract of original by Brahmachari.

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1. S-CARBOXYAKYLENE ISOTHIURONIUM SALTS OF ANTIMONYL TARTRATE. 